Synaptic transmission is usually thought of as occurring in the presynaptic to postsynaptic direction. Recently, it has been shown that the postsynaptic cell can communicate back with the presynaptic cell, in a process known as retrograde signaling. In this form of messaging, the postsynaptic cell releases a substance from its dendrites, which targets machinery in the presynaptic axon terminal. Thus, retrograde signaling allows neurons to control their own input, in both positive and negative feedback loops. Our preliminary evidence suggests such retrograde signaling exists at a hippocampal excitatory synapse, and is dependent on a rise in postsynaptic calcium. We will test this hypothesis using a combination of electrophysiology and glutamate photolysis. Given the importance of the hippocampus in many forms of learning and memory, this regulation might allow the network to increase its signal-to-noise ratio, and thus avoid being oversaturated. Moreover, the hippocampus has been heavily implicated in human disorders such as epilepsy, a pathological state characterized by runaway excitability. By enabling neurons to suppress their own excitation, retrograde signaling may have consequences related to health and disease, and provide one of the most basic, cellular forms of self control. PUBLIC HEALTH RELEVANCE: Retrograde signaling allows the neuron to regulate its own input, by communicating back with its presynaptic partner. In the hippocampus, such a messaging system would be particularly useful, since it could enable the neural network to prevent runaway excitability and oversaturation, common themes in human disorders such as epilepsy.